Brain death: Radiologic signs of a non-radiologic diagnosis

Clinical Neurology and Neurosurgery 185 (2019) 105465 Contents lists available at ScienceDirect Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro Brain death: Radiologic signs of a non-radiologic diagnosis a,⁎ b b c b Joseph Gastala , Deema Fattal , Patricia A. Kirby , Aristides A. Capizzano , Yutaka Sato , Toshio Moritanic a b c T Northwestern University, Department of Radiology, 676 N St Clair, Chicago, IL, 60611 University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242 University of Michigan, 1500 E Medical Center, Dr Ann Arbor, MI 48109 A R TICL E INFO A BSTR A CT Keywords: Brain death MR angiography CT angiography CT perfusion Ancillary testing Brain death is a clinical diagnosis characterized by the irreversible loss of neurologic function caused by global injury to the brain, including the brain stem. This is often caused by trauma and subarachnoid hemorrhage amongst other etiologies. This injury results in extensive cerebral edema, a rise in intracranial pressure, and eventual cessation of cerebral blood flow. Although brain death is a clinical diagnosis, ancillary and confirmatory tests are widely used. These are categorized into imaging that demonstrates absence of cerebral blood flow and electroencephalography that demonstrates absence of cortical electrical activity. Cerebral angiography, transcranial Doppler, and cerebral scintigraphy are the only imaging studies to have been validated by the American Academy of Neurology for diagnosis of brain death. However, characteristic findings on computed tomography, computed tomography perfusion, computed tomography angiography, magnetic resonance imaging, and magnetic resonance angiography may suggest the diagnosis. In this article, the clinical criteria, pathophysiology, pathology, and variations in current practice of brain death diagnosis are discussed, and the imaging findings of brain death are reviewed. 1. Introduction The concept of brain death was first described by Mollaret and Goulon in 1959 when they described “le coma dépassé” of comatose patients supported by mechanical ventilators with absent electroencephalographic (EEG) recordings, absent intracranial flow, or total brain necrosis at autopsy [1]. Before the advent of artificial cardiopulmonary support and mechanical ventilation, loss of heart and lung function were easily observable and sufficient to diagnose death. With the capability to maintain vital body functions after the brain had irreversibly ceased to function, a reexamination of the criteria of death followed [2]. In 1968, an ad hoc committee at Harvard Medical School expanded the medical definition of death based on neurologic criteria, defined as loss of function at the cerebral and brain-stem levels characterized by unresponsiveness and lack of receptivity, absence of movement and breathing, absence of brain-stem reflexes, a flat EEG, and by coma whose cause was known [2]. This effort was spurred by the moral, ethical, and legal controversies of organ transplantation in patients with irreversible coma and futile attempts at continued life support [2]. In the United States (US), the Uniform Determination of Death Act in 1981 provided a new legal and medical basis for defining death based on both cardiopulmonary and neurologic criteria [3]. Brain death was defined as the “Irreversible cessation of functions of the entire brain, including the brain stem.” Early recognition of brain death is important to expedite organ transplantation, provide closure for loved ones, and prevent futile medical interventions [4]. It comprises 1%–2% of deaths yearly in the US [5] and, in a large referral hospital, it may be diagnosed from 25 to 30 times per year [6]. The diagnosis of brain death is inherently a clinical diagnosis that is not always straightforward. In the US, the American Academy of Neurology (AAN) has promulgated the American Academy of Neurology Practice Parameters (AANPP) for the determination of brain death, first in 1995 and with an update in 2010, to establish guidelines and provide uniformity for the diagnosis [7]. Certain ancillary tests (electroencephalography [EEG], angiography, transcranial Doppler [TCD], and scintigraphy) have been validated by the AAN to be used as confirmation in situations of uncertainty although ancillary testing remains controversial. Although brain death is a clinical diagnosis, radiologists may encounter it with ancillary testing and Corresponding author. E-mail addresses: [email protected] (J. Gastala), [email protected] (D. Fattal), [email protected] (P.A. Kirby), [email protected] (A.A. Capizzano), [email protected] (Y. Sato), [email protected] (T. Moritani). ⁎ https://doi.org/10.1016/j.clineuro.2019.105465 Received 21 June 2019; Received in revised form 30 July 2019; Accepted 6 August 2019 Available online 12 August 2019 0303-8467/ © 2019 Elsevier B.V. All rights reserved. Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. perfusion pressure, intracranial circulation ceases [14,15]. Subsequently, loss of physiologic brain activity and electrocerebral silence are irreversible in the setting of brain death [17]. Post mortem examination of the brains of patients with irreversible brain injury can show uncal, central, and tonsillar herniations. This leads to compression of the brainstem with stretching and tearing of pontine perforating branches of the basilar artery resulting in pontine Duret hemorrhages (Fig. 2a). The brain is congested, soft to friable in texture, and has a dusky appearance [18] (Fig. 2b). Microscopy shows global cytotoxic and interstitial edema with diffuse neuronal ischemicanoxic injury (Fig. 2c). In the past, cerebral pathology of brain dead patients was referred to as “respiratory brain” with a dusky congested brain and extensive brain damage; the brain often was very friable upon removal from the skull [18–20]. In the modern era, with time to death and brain at autopsy shortened due to organ donation protocols, brain pathology is currently done within days of brain death diagnosis and the resulting pathology is different from the so-called respirator brain. The pathological findings in the modern era can be nonspecific and without pathognomonic features as previously recognized. More importantly, there may be lack of uniformly severe pathology. For example, Wijdicks found mild changes in one third of cerebral hemispheres and in one half of brainstems in brains studied within 36 hours of declaration of brain death [21]. imaging modalities including computed tomography (CT), CT angiography (CTA), CT perfusion (CTP), magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI), and magnetic resonance angiography (MRA) and must be familiar with the diagnosis. In this article, we review the clinical criteria and diagnosis of brain death, discuss the pathology and pathophysiology, and discuss the key imaging findings that can suggest and aid in the diagnosis. 2. Pathogenesis and pathology of brain death The inciting event of brain death is global irreversible injury to the brain [8]. In most adult series, traumatic brain injury and subarachnoid hemorrhage are the most common intracranial events leading to brain death [9,10]. In the intensive care unit, it is most commonly seen with large ischemic strokes or anoxic encephalopathy, often caused by an extracranial event such as cardiopulmonary arrest, resulting in prolonged and severe impairment of blood supply to the brain [5,8]. Any acute large space occupying lesion with brain herniation and compression of the brain stem can also cause brain death. Whatever the etiology, eventually global cerebral injury leads to marked brain swelling and destruction of brain parenchyma despite continued advanced life support. The most common mechanistic pathway leading to brain death is increasing intracranial pressure to the point of cessation of intracranial blood flow [11,12]. As a result of the inciting event, alterations in blood flow as well as oxygen and glucose supply leads to local or global injury [5]. Depending on the nature of the inciting event, there is increasing brain edema which can be intracellular (cytotoxic) secondary to hypoxia and changes in osmolar regulation [5] or extracellular (vasogenic) secondary to disruption of the blood brain barrier and loss of autoregulation [13]. As the brain is confined to a rigid structure, the cranium, there is limited ability to compensate for the increasing brain volume as edema progresses [14]. The main compensatory process for maintaining constant intracranial pressure (ICP) is CSF reduction, primarily by CSF resorption [14]. Once compensatory mechanisms are overcome, ICP rises and cerebral perfusion pressure decreases (Fig. 1). A threshold is finally reached at which small increases in brain volume lead to exponential rises in ICP [15]. When the volume of the expanding brain exceeds the skull volume, brain herniation will occur [13]. This causes compression and eventual irreversible damage to the brainstem leading to disruption of respiratory and cardiac centers as well as the reticular activating system [5], and this injury leads to loss of brainstem reflexes [16]. Respiratory failure from brainstem compression further exacerbates hypoxia and causes further increases in ICP[13]. When ICP exceeds arterial 3. Diagnosis Brain death is a clinical diagnosis that can only be determined when the clinical situation meets specific prerequisites [22]. First, there must be clinical or neuroimaging evidence of an acute catastrophic event that could cause clinical brain death; this is commonly demonstrated on CT scanning. Secondly, complicating medical conditions that may confound clinical assessment must be excluded, including severe acid-base disturbances, electrolyte imbalances, or endocrine disturbances. These must be investigated even if there is an abnormality discovered on imaging. Third, there must be no drug intoxication or poisoning. Finally, hypothermia must be excluded, and the core temperature must be greater than 36 °C. Once these prerequisites are met, clinical examination is appropriate. The diagnosis of brain death is made with documentation of the three cardinal findings: coma, absence of brain-stem reflexes, and apnea (Table 1) [8]. Coma is assessed by performing a complete neurological examination in accordance with the AAN guidelines [8], which includes testing for absent responses to verbal, visual and painful stimuli on the face and extremities. Absence of brain-stem reflexes is assessed by examining the pupils, ocular movements, facial motor response, and Fig. 1. Intracranial pressure and intracranial volume regulation. Total intracranial volume is comprised of the volume of the cerebrospinal fluid (CSF), the brain, intracellular and extracellular water, blood volume and any volume contributed by a possible tumor, hematoma or other mass lesion (8, 12). An increase in any one of these components must be accompanied by a decrease in another. Increasing intracranial pressure (ICP) causes arteriolar vasodilation to maintain cerebral perfusion pressure (CPP) also resulting in increased cerebral blood volume (CBV). CPP is the driving arterial pressure gradient across cerebral vasculature demonstrated by the following relationship: CPP = Mean arterial pressure (MAP)–ICP (9). With decreasing CPP, arterial vasodilation occurs to maintain cerebral blood flow in a process called autoregulation. However, this vasodilation leads to increased cerebral blood volume (CBV), and a vicious cycle may occur in which further rises in CBV cause further increases in ICP (9). 2 Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. Fig. 2. Gross pathology and microscopy in cases of clinically diagnosed brain death. (a) Duret hemorrhages after compression of the brainstem. (b) The brain increasingly takes on a dusky, congested, and discolored appearance. (c) Microscopy demonstrates cytotoxic edema in the brain stem with vacuolation of the white matter neuropil (hematoxylin-eosin stain, original magnification ×400) but the patient does meet clinical criteria) or false-negative results (clinical brain death but confirmatory test is negative) [22] (Tables 2 and 3). Ancillary tests can be divided into tests that evaluate brain function, such as EEG, and tests that evaluate intracranial blood flow, such as imaging studies [17]. The tests which have been investigated, validated, and approved by the AAN are cerebral angiography, TCD, and cerebral scintigraphy [8]. The decision to use a specific ancillary test is dependent on many factors, including availability, safety of transport, and diagnostic accuracy [25] and there is no evidence to support use of one ancillary test over another. Further research would be helpful to establish guidelines in this regard if ancillary testing is used. The most specific confirmatory findings on imaging are related to the cerebral circulatory arrest caused by increased ICP [26], with loss of CBF. Table 1 Brain death diagnostic criteria [8]. Clinical Criteria Absence of motor responses to painful stimulus Absence of response to supraorbital nerve pressure, temporomandibular joint pressure, sternal rub, or nail-bed pressure Absence of brain stem reflexes Absence of pupillary responses, corneal reflexes, caloric responses, gag reflexes, coughing in response to tracheal suctioning, sucking and rooting reflexes Apnea Absence of respiratory drive Validated confirmatory tests Confirmation of loss of electrical activity Electroencephalography Demonstration of loss of cerebral blood flow Cerebral angiography Transcranial Doppler ultrasonography Cerebral scintigraphy 4. Variations in clinical practice There is no international consensus for the diagnosis of brain death and the role of ancillary testing as there are wide variations in guidelines and legislation [17,27]. Even though the lack of uniformity in brain death determination has improved over time [7] discordant practices still abound [28–30]. Some advocate the diagnosis can always be made clinically if the examination is performed properly and ancillary testing is unnecessary [22]. About half of European countries routinely require ancillary tests before brain death can be diagnosed [27]. Others require ancillary testing only when confounding factors interfere with the clinical determination [31]. In the US, there is no federal legislation regarding the determination of the diagnosis, and legal guidelines vary state by state [5,8]. In 2010, the AAN updated the AANPP with the attempt to standardize the diagnosis, and reiterated that the diagnosis of brain death can be made without ancillary testing, also highlighting the as of yet unproven role of newer ancillary methods such as CTA [7]. pharyngeal and tracheal reflexes [8]. Finally, a positive apnea test is the absence of breathing when the PaCO2 reaches a target level of 60 mmHg or increases 20 mmHg above the baseline after 8–10 min of disconnection from the ventilator [8,23]. The key distinction between adult and pediatric brain death determination is the addition of a second, confirmatory examination including apnea testing 12 to 24 hours after the initial examination with pediatric patients [24]. If specific components of the clinical testing or the apnea test cannot be reliably evaluated, or are inconclusive, confirmatory and ancillary testing can assist in the diagnosis. The most common indication confirmatory testing is performed is the failure to complete the apnea test [22] and other indications include situations in which cranial nerves cannot reliably be assessed, such as in patients with skull base or facial trauma or patients with pre-existing cranial neuropathies [17]. Ancillary tests can lead to false-positive (ancillary test suggests brain death 3 J. Gastala, et al. Table 2 Comparison of imaging modalities [17,25,39,42]. Modality Technical Aspects Findings Advantages Disadvantages Potential Pitfalls Cerebral Angiography −Separate injections are performed in both common or internal carotid arteries as well as vertebral arteries −Lack of opacification of intracranial ICAs and vertebral arteries −Excellent for demonstrating intracranial blood flow −Validated by AAN -Considered “gold standard” −False positive in hypotensive patients -Stasis filling Cerebral Scintigraphy −Tc-99 HMPAO or ECD most commonly used -Up to 30 mCi radiotracer may be used -Validated by AAN Transcranial Doppler −2 MHz probe -Bitemporal and suboccipital acoustic windows are utilized −May be performed on 1.5 T or 3 T magnet −Absence of cerebral uptake, cerebellar uptake, or both -Hot nose sign -Progressive loss of forward flow − Operator dependent − Limited availability − Contrast load − Radiation dose − Limited anatomic detail - Possible damage to transplant organs with vessel occlusion −No anatomic detail -Limited availability MRI Conventional 4 DWI SWI/GRE MRA CT Noncontrast CTP -Diffuse decrease in ADC extending to the brainstem −Transcerebral and transcortical vein signs -Prominent medullary veins -Lack of flow above supracliniod ICAs, no contrast distal to level of ACA and M1 segment of MCA −Brain herniation patterns -Mass, hemorrhage, edema −Lack of opacification of ICVs is most sensitive -4 and 7 point scales for intracranial opacification -Matched decrease in CBF and CBV extending to the brainstem −No radiation -Provides anatomic information −Widely Available −Rapid -Provides anatomic information −Operator dependent -Acoustic window may be limited −Time consuming −Expensive −Not widely available −Difficult to perform on ventilated patients -Variable criteria for intracranial circulatory arrest −Radiation dose −Contrast load with CTA/CTP -Variable criteria for intracranial circulatory arrest −False positive in hypotensive patients −False negative in decompressive craniectomy or other reason for intracranial decompression -Stasis filling Clinical Neurology and Neurosurgery 185 (2019) 105465 CTA −Protocol typically includes noncontrast CT brain, with 20 s arterial and a delayed 60 s venous phase −Transtentorial and foramen magnum herniation −Absent intracranial vascular flow voids −Poor white/gray matter differentiation -MR hot nose sign −No radiation -Validated by AAN -False negative in decompressive craniectomy or other reason for intracranial decompression -False negative in decompressive craniectomy or other reason for intracranial decompression −MRI artifacts Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. Table 3 Sensitivity and specificity of imaging modalities[8,38,47,59–61,64,69,76–79]. Modality Sensitivity/Specificity Number of reported proven brain death patients Number of reported non brain death patients with a positive result Cerebral Scintigraphy Transcranial Doppler MRI/A CTA CTP 70–100%;97-100% 73–100%;75-100% 93–100%;100% 62–100%;NAa 86–100%;NAa 274; 226 positive, 48 negative 1311; 1137 positive, 174 negative 64; 59 positiveb, 5 negative 467c; 391 positive, 76 negative 38; 35 positive, 3 negative 0 6 0 1d 0 a All studies but one included only patients which were already clinically diagnosed with brain death. One study of 22 patients included a small number (n = 2) of patients which were not prospectively diagnosed with brain death. b Positive result with no flow above supraclinoid ICA on MRA or loss of flow void on conventional MRI c Includes studies only for which a 4 point scale could be determined, i.e. two phase exam with explicit examination of 4 point criteria. d A case report of a patient unable to complete apnea testing. A CTA was positive for brain death, but a TCD 9 h following was negative. An HMPAO SPECT study 3 h of after the TCD was positive for brain death. Fig. 3. Clinically diagnosed brain death in a 43-year-old male with aortic dissection, postoperative course complicated by ischemic bowel. (a) Tc-99 m HMPAO scintigraphy at the same day of the CT demonstrates no intracranial vascular flow. (b, c) Axial and sagittal CTA images demonstrate bilateral transtentorial (arrows) and tonsillar herniation)(arrowhead). Note a lack of opacification of intracranial circulation with no opacification in the internal cerebral veins and middle cerebral arteries, findings that confirm brain death. entry of these arteries to the skull [33,34]. Destruction of the intracerebral vascular tree in conjunction with necrosis related to brain injury also contributes to the absence of intracranial flow. The flow pattern in brain death is the reverse of the normal cerebral vascular filling, in which the low resistance intracranial arteries fill before the higher resistance extracranial arteries. In brain death, external circulation remains patent, filling rapidly and early. In certain patients, supratentorial circulation can cease but persistent and delayed posterior fossa blood flow can be seen, which may result from the protective effect of the cerebellar tentorium from increased hemispheric pressure [35]. Despite the advantages of accuracy and resolution, angiography is invasive, time-consuming, and dependent on the availability and skill of the operator. Additionally, angiography may inadvertently obstruct flow within the remaining vessels and cause damage to transplantable organs of brain death donors. Pitfalls can occur when the patient does Actual practice patterns also vary widely despite some established guidelines. For example, in the US, despite guidelines established by AANPP 2010, a study of patients diagnosed with brain death over a one year period found that at least one ancillary test had been performed in about 65.5% of patients, with CTA being performed in 12.8% of those patients [28]. Therefore, despite the controversial and uneven role ancillary testing plays in the diagnosis, imaging is still widely used. 5. Imaging in brain death 5.1. Cerebral angiography Cerebral angiography is considered the gold standard for assessment of intracranial circulation [32]. In the setting of brain death, flow is obstructed in the internal carotid and vertebral arteries due to increased ICP, and angiography will show no intracerebral filling at the level of 5 Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. include operator dependence as well as dependence on the available acoustic window[41]. Cerebral scintigraphy Multiple radiotracer uptake patterns have been described with cerebral scintigraphy in the setting of clinical brain death. Typical agents used include 99mTc hexamethylpropyleneamine ozime (HMPAO) or 99mTc ethylene cysteine diethyl ether (ECD) with planar or single photon emission CT (SPECT) [42]. Demonstration of no uptake within the cerebrum and cerebellum provides straightforward confirmation [43] (Fig. 3a). Another uptake pattern that has been described is the preservation of cerebellar perfusion without cerebral perfusion. All documented cases with this pattern have eventually been diagnosed with brain death, but this is still considered an equivocal finding [26,43]. A rare pattern is absent cerebellar but preserved cerebral uptake [44], which is also equivocal. The “hot nose” sign is another finding referring to increased uptake in the nasal area with nonfilling of intracranial arteries and can be seen with brain death [45,46]. As with the other ancillary tests, cerebral scintigraphy has significant false positive and false negative results when compared to the clinical exam [22,47]. 5.3. CT In patients suspected of brain death, initial interpretation of the noncontrast CT scan is essential in helping determine the underlying cause [48] (Fig. 4a). This may demonstrate single or multiple hemispheric lesions, intracerebral hemorrhage, stroke, tumor, or edema, corresponding to the initial inciting event. A positive finding on CT, however, still requires careful consideration of any confounding factors [48]. A negative CT scan should cast doubt on the diagnosis, although it still may be falsely normal in certain patients after cardiorespiratory arrest and acute stroke [9]. The noncontrast CT is of limited use beyond radiologic evaluation for an inciting cause, as brain edema, trauma, and ischemia can occur without clinical brain death. Fig. 4. 57-year-old female with brain death. Initially presented with headaches and subsequently became unresponsive. (a) Axial noncontrast CT demonstrates subdural hematoma with midline shift. (b) Coronal CTA maximum intensity demonstrates external carotid artery branches and a lack of opacification of intracranial circulation. 5.4. CTA/CTP CTA has gained attention in the evaluation of brain death as it is a non-invasive and widely available technique that clearly demonstrates contrast medium in the vascular system to evaluate cerebral circulation and is relatively less operator dependent than conventional angiography [49] (Fig. 3b-d). Several vessels have been proposed for the demonstration of intracerebral circulatory arrest in both arterial and venous phases [50–54]. Three-dimensional reconstruction images of CTA can demonstrate external carotid artery branches and a lack of opacification of intracranial circulation (Fig. 4b,c). Multiphase spiral CTA provides both anatomical and functional information of brain death (Fig. 5a-c). In the seminal study by Dupas et al., 14 clinically brain dead patients were scanned in two phases: twenty seconds and then 54–60 s after initial injection [50]. Brain death diagnosis in this study relied on a score based on lack of opacification of 7 intracerebral vessels: the pericallosal arteries, cortical segments of the middle cerebral arteries (MCA), internal cerebral veins (ICV), and 1 great cerebral vein. Lack of opacification of these vessels indicated stagnation and arrest of contrast medium at the level of internal carotid and vertebral arteries with absence of venous blood return. There were 2 brain dead patients who had MCA M1 segment weak opacification, including one where angiography showed no flow (false negative). The specificity was 100%, as compared to CTAs of healthy volunteers used as controls. On the basis of this study, this was accepted as one of the ancillary tests for brain death diagnosis in France and Netherlands [49]. Additionally, Austria, Switzerland, and Canada adopted its use in confirmation of brain death, even though follow up studies did not replicate the results, with sensitivity ranging from 11 to 48% although not meet clinical criteria yet the cerebral angiogram is consistent with brain death (false positive test) [22], or, conversely, when there is persistence of intracranial circulation in the clinical setting of brain death, which has been documented in many case reports (false negative test) [36]. This persistence of blood flow in brain death can affect not only the interpretation of cerebral angiograms, but also other imaging methods (such as CTA and MRA) that evaluate cerebral blood flow and cerebral perfusion. One of the most common scenarios for this phenomenon is when the imaging study has been performed after clinical brain death, but before the ICP exceeds systolic pressure [36]. 5.2. TCD sonography TCD is inexpensive and noninvasive and can be performed at the bedside. It is a validated confirmatory test, with sensitivity varying from 91-99% and specificity of 100% [37]. A systematic review by Chang et al. showed pooled sensitivity and specificity of 90% and 98%, respectively, for showing cerebral circulatory arrest [38]. Moreover, sensitivity increases with time, reaching 100% after 36 h [22]. Yet, false positive and false negative results (using the clinical exam as reference) are well documented [22]. TCD in brain death shows cerebral circulatory arrest in the middle cerebral arteries, indicated by characteristic flow patterns without forward flow progress [37,39,40]. Disadvantages 6 Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. Fig. 5. 42-year-old female with brain death. Presented with diffuse subarachnoid hemorrhage. (a, b) Axial 3D multiphase CTA images demonstrate delayed opacification of intracranial circulation (a: 24 sec, b: 43 sec after contrast injection). (c,d) CT perfusion images demonstrate matched and decreased CBV (c) and CBF (d) in the supratentorium and posterior fossa including the brain stem. there was some variability in the diagnostic criteria and contrast phase timing [51–53]. Frampas et al. introduced a more simplified 4 point score based on lack of opacification of the cortical segments of the MCAs and ICVs [54]. The 4 point scale was more sensitive than the 7 point scale, with a sensitivity of 85.7% versus 62.8%, respectively. Subsequent studies have also found absence of opacification of the MCAs and ICVs to be more sensitive than the 7 point scale for demonstrating brain death [55,56]. CTP in addition to CTA, with a focus on the brain stem, may be useful as an additional ancillary tool [57] (Fig. 5d,e). This was demonstrated in a retrospective study of 11 patients by Shankar et al. that yielded a sensitivity of 100% with CT perfusion in addition to CTA, using criteria of no flow or matched CBF and CBV reduction within the brainstem. Comparatively, the sensitivity of both the 4 and 7 point scales in this study was 72.7% [57]. Another study by Escudero et al. of 27 patients showed a sensitivity of 89% using CTP and CTA [58]. These studies suggest that CTP in addition to CTA may increase sensitivity, but this needs to be validated on a larger scale. Two systematic reviews have assessed the accuracy of CTA in the diagnosis of brain death [56,59], and another more recent systematic review has assessed CTA in addition to CTP [60]. In a Cochrane review by Taylor et al., the sensitivity in 8 studies involving 337 patients was low at 84% compared to clinical testing; when using only the 4-point scale, sensitivity was only 85%. Specificity could not be calculated as all brain dead patients were diagnosed with clinical assessment, and there were no patients for whom CTA was performed without the clinical diagnosis. The authors concluded that CTA “may be useful… assuming that clinicians are aware of the relatively low overall sensitivity” [56]. In a study by Kramer [59], the pooled sensitivity was 62% for venous phase and 84% for arterial phase imaging in 12 studies involving 541 patients when compared to clinical testing, cerebral angiography, or radionuclide imaging. The most recent systematic review by Brasil et al. revealed a sensitivity of 87.5% in 8 studies involving 322 patients using the 4 point scale but found no benefit for adding CTP based on 2 studies [60]. Given the low sensitivity in these systematic reviews, a substantial portion of cases would not be diagnosed as brain death. In all these studies performed, absence of opacification of the internal cerebral veins was the most sensitive parameter for the diagnosis of brain death [52,56,60], although none have evaluated ICV a priori for the diagnosis. A major limitation in nearly all the previous studies is that all studied patients had already been diagnosed with clinical brain death and there was no inclusion of patients without the diagnosis. Therefore, specificity could not be determined on prior studies. A recent study by Garrett et al. is the first to include a control group of neurologically critically injured patients which did not meet the clinical criteria for brain death. While this control group was small (n = 2), the authors 7 Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. Fig. 6. Clinically diagnosed brain death after imaging in an 11-year-old female with anoxic brain injury. (a) Sagittal T1 weighted image demonstrates marked diffuse brain edema with tonsillar herniation (arrow) and brain sagging (arrowhead). (b) Axial T2-weighted images at the level of the pons shows diffuse obliteration of cortical sulci and loss of flow voids within the bilateral ICAs (arrows). (c) Axial susceptibility-weighted image demonstrates Duret hemorrhages in the center of the pons. (d) Axial ADC map demonstrates prominently decreased ADC in the entire brain stem extending to the medulla (0.25 × 10−5 mm2/ sec) and cerebellum. (e) Axial susceptibility-weighted image demonstrate transcortical (arrows) and transcerebral (arrowheads) vein signs with prominent medullary veins. found a specificity and positive predictive value of 100% compared to the clinical exam using the 4 point scale [61]. Despite its advantages, CTA is not yet widely accepted as an ancillary test for the diagnosis of brain death with the main obstacle being insufficient diagnostic confidence [53]. There is also no consensus regarding the radiographic criteria used to demonstrate absence of intracranial blood flow [17]. One major limitation is persistent contrast enhancement of cerebral vessels, which could be interpreted as persistence of intracranial flow [53], as has been described with cerebral angiography. This can occur in patients who have had decompressing fractures or craniectomies, ventricular shunts, as well as brain herniation [36,62]. 5.5. MRI/MRA MRI can demonstrate some characteristic findings in the setting of brain death. Orrison et al. first identified 6 signs on MRI: 1) transtentorial and foramen magnum herniation, 2) absent intracranial vascular flow voids, 3) poor gray matter/white matter differentiation, 4) absent intracranial contrast enhancement, 5) carotid artery enhancement 8 Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. Fig. 7. 32-year-old man with brain death. Initially presented with headache, and. CSF findings consistent with viral infection. (a) ADC map reveals marked decreased ADC in the white matter (0.21 × 10−3 mm2/sec) and decreased ADC in the cortex (0.51 × 10−3 mm2/sec). Note diffuse obliteration of cortical sulci. Axial diffusion weighted image (not shown) showed diffuse increased signal intensity (b) Decreased ADC is observed in the pons (0.30 × 10−3 mm2/sec) but not involving the cerebellum. (c) Intracranial time of flight MR angiography demonstrates external carotid artery branches and loss of vascular flow of internal carotid arteries. (d) Dynamic contrast MR angiography shows loss of vascular flow within the supraclinoid internal carotid arteries but reveals opacification of intracranial vertebral and basilar arteries. (intravascular enhancement sign), and 6) prominent nasal contrast and scalp enhancement (MR hot nose sign) [63] (Fig. 6a, b). Evidence of brain stem injury with Duret hemorrhages is also well visualized on gradient recalled echo (GRE) and susceptibility weighted imaging (SWI) (Fig. 6c). Any of these findings when in isolation, however, are not specific for brain death. For example, transtentorial and foramen magnum herniation as well as poor gray matter/white matter differentiation may also be observed in patients with severe hypoxic brain damage in the absence of brain death [64]. DWI shows diffuse decrease in the ADC values of both white and gray matter [65] (Fig. 7a). Pathologically, the decreased ADC areas specifically represent cytotoxic edema. Low ADC values are greater in white matter than gray matter for both cerebral and cerebellar hemispheres [66], which may reflect cytotoxic edema of different cellular components in the gray (neurons and glial cells) and white matter (myelin sheaths, glial cells and axons). Diffusion restriction usually extends to the brain stem and, variably, the cerebellum [66] (Figs. 6d, 7b). Extensive diffusion restriction, however, may occur in other situations, such as bilateral carotid artery occlusion [67], and this should be correlated with other findings of brain death. Another confounding factor is the difference in ADC values between MRI scanners and DWI protocols, making comparison of absolute threshold values difficult [68]. Findings on SWI and GRE include the transcerebral vein and transcortical vein signs [69] (Fig. 7d) as well as prominent medullary veins (Fig. 7d). The transcerebral vein sign refers to multiple and/or branching dark structures extending through the cerebral hemispheres parallel or perpendicular to the outer wall of both lateral ventricles; the transcortical vein sign is accentuated visualization of hemispheric cortical veins [70]. These have been described in acute stroke among other etiologies, caused by increased oxygen extraction fraction with increased deoxyhemoglobin in capillaries and veins [69,71]. Although these findings can be seen in brain death they are not specific [69]. Time of flight (TOF) MRA (Fig. 7f) and dynamic contrast enhanced MRA (Fig. 7g) have also been studied in brain death. Ishii et al. first demonstrated findings on TOF MRA, showing absence of cerebral vessels above the level of the supraclinoid ICAs, indicating cessation of blood flow[64]. The first study using gadolinium enhanced MRA by Luchtman et al. showed no intracranial contrast above the level of the anterior cerebral artery and M1 segment of the MCA, consistent with the findings on TOF MRA [72]. More recently, spin-labeling perfusion MRI has emerged as a technique for measuring cerebral blood flow. This method generates a perfusion image by subtracting signal in labeled protons in feeding arterial vasculature from background signal from unlabeled brain tissue [73]. This was found to satisfy criteria of brain death in a small series of patients (Fig. 8a, 8b) [74]. Similar to CTA, there is insufficient diagnostic confidence with MRI and MRA to be used routinely as a confirmatory test for brain death. Disadvantages include length of scanning time, lower availability, difficulty obtaining the study on a ventilated patient, and cost. 5.6. Future directions Further research is necessary to establish validity of CTA and MRA for determination of brain death. Specifically, greater consensus is needed to establish radiographic criteria used to identify cessation of brain blood flow, including prospective assessment of lack of opacification of ICVs for the diagnosis. Other techniques, including CTP and ASL, have shown some promise, and further studies validating these techniques is needed. Finally, resting state functional MRI is a technique that can evaluate functional neuroanatomic connectivity not possible with conventional imaging and provides a tremendous amount of additional information. This neuroanatomic connectivity has been shown to be decreased in vegetative state and brain death patients in a single-case study [75]. 9 Clinical Neurology and Neurosurgery 185 (2019) 105465 J. Gastala, et al. Although this is not as widely available as other imaging modalities, further studies with greater power may be fruitful in establishing the role of this technique in the diagnosis. [27] Conclusions [28] Brain death is caused by global irreversible brain injury. Early recognition is important to provide closure for loved ones, prevent unnecessary interventions, and support organ transplantation if applicable. Brain death remains a clinical diagnosis. However, there are circumstances in which confirmatory tests may be helpful. 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